Background Synchronous metastases are considered a negative prognostic factor in patients with metastatic colorectal cancer (CRC). We investigated the outcomes of stage IV CRC patients undergoing complete gross resection (R0/1) of both the primary tumor and the metastases under the guidance of a multidisciplinary team (MDT). Methods All CRC patients with synchronous metastases were retrieved from a prospective database. Patients treated from 2006 to 2017 who underwent complete resection were analyzed. Various factors, including multiple metastatic sites and complex procedures, were investigated. Univariate and multivariate overall survival (OS) calculations were performed. Results Of 330 consecutive patients with synchronous metastases, 101 (30.6%) achieved an R0/1 status including 12 (11.9%) patients with multiple metastatic sites. Complex procedures were necessary in 45 (44.6%) patients. Five‐year OS was 53.0% for the R0/1 patient group. Multivariate analysis could not detect factors associated with prognosis. Conclusions With modern treatment, the prognosis of patients with synchronous CRC metastases can be improved. Decisions made by a MDT offered one‐third of patients a potentially curative approach to their stage IV disease. Despite the treatment of a high rate of patients with complex metastases necessitating complex procedures, we achieved a favorable 5‐year OS rate.
Partial unilateral penile thrombosis of the corpus cavernosum is a very rare disease and occurs mainly in young men. The leading symptoms are perineal swelling and pain, while erectile function is maintained. The exact pathogenesis of this condition remains unclear. This is the first report of partial penile thrombosis due to hyperhomocysteinemia. Magnetic resonance imaging is the procedure of choice in diagnostics of partial penile thrombosis. For the treatment of partial penile thrombosis, surgical procedures are increasingly being replaced by more conservative treatments with analgesics and heparinization. Both surgical and conservative treatment provides excellent outcomes. A table provided in this article lists all published cases and refers to pathogenesis, diagnostics, therapy, and follow-up.
The incidence of AML increases with age. More than half of the patients (pts) are over 60 years (y) at time of diagnosis. On the other hand, elderly pts are clearly under-represented in the literature. The AML 97 study was designed to register all pts aged 60 and more with newly diagnosed AML. Subsequently, pts were allocated to one of the 3 parts of protocol dependent on Karnofsky’s index (KI). Methods: Since March 1998 to October 2005 a total of 644 pts were enrolled in the study, 496 (77%) pts were allocated to the curative, 115 (18%) to the palliative and 33 (5%) to the supportive part of the protocol. Pts characteristics between the 3 groups differed significant in respect to age (p<10−6) and KI (p<10−6). Median age of pts was 66 y (range 60–88 y), 76 y (range 64–90 y) and 77 y (range 63–97 y) for the curative, palliative and supportive protocol respectively. Curative treatment consisted of one (in case of PR of two) courses of induction (AraC 2 g/m2 iv day 1,3,5,7 in combination with Mitoxantrone 10 mg/m2 iv day 1–3) followed by 2 consolidation courses (AraC 240 mg/m2 iv day 1–5 combined with Mitoxantrone 10 mg/m2 iv day 1–2). Palliative treatment consisted of Idarubicin 10 mg po day 1 in combination with either Thioguanine 40 mg po day 1–5, or AraC 80 mg sc day 1–5 or Etoposide 100 mg po day 1–5. As supportive treatment only transfusions were applied. Results: The present analysis based on 550 eligible and evaluable pts, 420 after curative, 98 after palliative and 32 after supportive treatment. After intensive chemotherapy, 100%, 74,5%, 65,4% and 52,2% pts achieved CR with favourable, normal, other or unfavourable karyotype, respectively. The high CR rate was accompanied by an acceptable early death (ED) rate of 17% for all intensive treated patients. The actually event free survival (EFS) after 4y is 0,45 (±0,11), 0,12 (±0,03), 0,11 (±0,05) and 0,05 (±0,03) for favourable, normal, other and unfavourable cytogenetics, respectively. The median overall survival (OS) is actually not reached for the favourable karyotype (range 4–87 months), amount to 13 months (m) for normal (range 1–105 m) and other (range 4–88 m) karyotype and 7 months (range 1–88 m) for unfavourable karyotype. In a multivariate analysis, cytogenetics at diagnosis were the most important and powerful prognostic factor for CR (p=0,002), EFS (p=10−6) and OS (p=10−5). The results of pts after palliative or supportive therapy were clearly inferior with median OS of 54 and 11 days, respectively. Conclusion: Our registration study shows that CR can be induced in a high proportion of elderly AML pts with acceptable ED rates in the curative arm. Despite high CR rates, quality of CR was not reached for improving EFS and OS. So a new protocol with the option of allogeneic PBCST after reduced conditioning was successfully started. The results after palliative therapy are disappointing. New strategies like demethylation or targeted therapy are necessary for these elderly pts not eligible for intensive chemotherapy.
Outcome of elderly patients with AML is usually poor. Increased incidence of high risk AML and intolerance against dose escalation are the main causes for treatment failure. Pharmacokinetic measurements indicated that intracellular Ara-CTP formation is saturated at much lower infusion rates than used in high dose AraC schedules, probably causing AraC accumulation in the plasma and increased toxicity. Therefore, the East German Study Group (OSHO) used intermediate doses of AraC delivered at the presumptive saturating infusion rate over a prolonged period of time. The same schedule was applied to younger (≤60 years of age, AML 96) and older (>60 years of age, AML 97) patients with AML. In the present evaluation, determining factors for complete remission rate and hematopoietic reconstitution were identified. Methods: All 690 patients entered in the AML 96 (n=370) and AML 97 (n=320) study of the OSHO and treated with one or two courses of induction therapy (AraC 2 g/m2 iv on day 1,3,5,7 in combination with idarubicine 12 mg/m2 day 1–3 or mitoxantrone 10 mg/m2 iv day 1 to 3) followed by 2 consolidation courses were evaluated. The following baseline variables were studied in univariate analysis for their impact on CR rate: sex (M vs. F), age (≤ 60 years vs. >60 years; continuous variable), cytogenetics at diagnosis (normal, favourable, unfavourable and others), disease classification (de novo or secondary AML), WBC (<2/2–90/>90 x 109/l), FAB-classification (M0/M1/M2/M3/M4/M5/M6/M7), LDH (≤ 2 x ULN vs. > 2 ULN) and the use of G-CSF (yes or no). Factors significant in this analysis were included in a multivariate model (logistic regression). Hematopoietic reconstitution was defined as the first of two consecutive days with leucocytes >1000/μL and platelets >50000/μL. Results: As shown in the multivariate analysis, the most important and highly significant parameter for CR rate was cytogenetics at diagnosis (p=10−11) followed by disease classification (de novo or secondary AML; p=0,001), WBC (p=0,003) and sex (p=0,018). In contrast, we could not demonstrate any significant influence of age (p=0,64), G-CSF (p=0,16) and FAB classification (p=0,38) on CR rate. Significant factors for the recovery of leukocytes were the use of G-CSF (p= 10−12), cytogenetics (p=10−4) and disease classification (de novo or secondary AML; p=0,04). AML classification (de novo or secondary AML; p=0,00002) and cytogenetics (p=0,001) but not age (p=0,17) were determinants for platelet recovery. Conclusion: Cytogenetics at diagnosis and disease type (de novo vs. secondary) were the most important determinants for CR rate using intermediate dose AraC. We could not demonstrate any influence of age on CR rate and hematological recovery.
Clinical trials on different cytarabine doses for treatment of AML provide evidence of a dose response effect, but also for increase toxicity after high dose AraC (HDAC). Pharmacokinetic measurements of cytarabine-triphosphate (AraC-CTP), which is the most relevant cytotoxic metabolite of AraC, have revealed its formation in leukemic cells to be saturated with infusion rates above 250 mg/m2/h, this being significantly lower than used in HDAC schedules. Methods: Based on a pharmacological model and encouraging results of a phase II study we conducted a prospective randomized multicenter clinical trial comparing the effects of two different application modes of AraC in patients up to 60 years with untreated newly diagnosed AML. Patients were randomized to receive AraC at two different infusion rates (IR) during induction and consolidation treatment: arm A/experimental: 1 × 2 g/m2/d AraC over 8 hours (IR 250 mg/m2/h) arm B/standard: 2 × 1 g/m2/d AraC over 3 hours (IR 333 mg/m2/h). Induction and first consolidation consisted of AraC (days 1, 3, 5, 7) in combination with an anthracycline (Idarubicine 12 mg/m2 or Mitoxantrone 10 mg/m2, days 1–3). The final dosage points (AraC day 7 and anthracycline day 3) were excluded from the second consolidation. The third consolidation consisted of either allogeneic or autologous stem cell transplantation or of chemotherapy identical to second consolidation. Results: From 02/97 to 04/02 419 patients were enrolled in the study. The present analysis is based on 361 eligible and evaluable patients with a median follow up of 7 years. CR was reached in 249/361 (69%; 95%CI: 65%–74%) patients. No statistically significant differences were detected between arms A and B with regard to CR-rate (69% vs 69%) or early death rate (11% vs 8%). Hematological recovery of median white blood cell count (WBC) > 109/l and median platelets (plt) > 50 × 109/l revealed no difference between arms A and B after induction (WBC day 22 vs 22, p=0,68; plt day 25 vs 26, p=0,41) and consolidation (WBC day 28 vs 27, p=0,07; plt day 42 vs 40, p= 0,58). The event free survival (EFS) after 5 years is 0,25 ± 0,03 % for all patients with an overall survival of 0,31 ± 0,03 % after 5 years. For the purposes of analysis, the 83 transplant patients (23 allogeneic MRD, 14 allogeneic MUD and 46 autologous) were censored at time of transplant. No statistically significant difference between arms A and B in regard to EFS (0,25 ± 0,04 vs 0,25 ± 0,04, p=0,99), relapse incidence (0,63 ± 0,06 vs 0,60 ± 0,06, p=0,89), overall survival (0,32 ± 0,04 vs 0,30 ± 0,04, p=0,44) and therapy associated mortality (0,18 ± 0,04 vs 0,17 ± 0,03, p=0,95) were detectable after adjustment of prognostic factors. An analysis of risk factors by multivariate cox regression model confirmed cytogenetics at diagnosis to be the most important risk factor for CR rate (p<10−6) and for EFS (p<10−6). Other significant prognostic factors for EFS evaluated in the multivariate analysis were de novo vs secondary AML (p=0,0001), WBC (continuous) (p=0,001), LDH (>1–4 × vs other ULN) (p=0,008) and FAB classification (FAB M0,6,7 vs FAB M1,2,4,5) (p=0,0005). EFS after 5 years shows a significant correlation to cytogenetics (p<10−6) with 0,71±0,1, 0,27±0,05, 0,20±0,06 and 0,03±0,03 for favorable, normal, other and unfavorable cytogenetic karyotype, respectively. Conclusion: We conclude that the application of AraC at the presumptive saturating infusion rate of 250 mg/m2/h results in comparable remission rates, toxicity, event free survival and overall survival as compared to the standard IR with 333 mg/m2/h.
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